During obesity, macrophages infiltrate the breast tissue leading to low-grade chronic inflammation, a factor considered responsible for the higher risk of breast cancer associated with obesity. Here, we formally demonstrate that breast epithelial cells acquire malignant properties when exposed to medium conditioned by macrophages derived from human healthy donors. These effects were mediated by the breast cancer oncogene IKKε and its downstream target-the serine biosynthesis pathway as demonstrated by genetic or pharmacological tools. Furthermore, amlexanox, an FDA-approved drug targeting IKKε and its homologue TBK1, delayed in vivo tumour formation in a combined genetic mouse model of breast cancer and high-fat diet-induced obesity/inflammation. Finally, in human breast cancer tissues, we validated the link between inflammation-IKKε and alteration of cellular metabolism. Altogether, we identified a pathway connecting obesity-driven inflammation to breast cancer and a potential therapeutic strategy to reduce the risk of breast cancer associated with obesity.

中文翻译：

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巨噬细胞通过 IKKε/TBK1 激酶和丝氨酸生物合成途径诱导乳腺上皮细胞的恶性特征。

在肥胖期间，巨噬细胞渗入乳房组织，导致低度慢性炎症，这一因素被认为与肥胖相关的乳腺癌风险较高。在这里，我们正式证明乳腺上皮细胞在暴露于由来自人类健康供体的巨噬细胞调节的培养基时会获得恶性特性。这些作用是由乳腺癌癌基因 IKKε 及其下游靶标——丝氨酸生物合成途径介导的，如遗传或药理学工具所证明的那样。此外，FDA 批准的靶向 IKKε 及其同源物 TBK1 的药物 amlexanox 在乳腺癌和高脂饮食诱导的肥胖/炎症的组合遗传小鼠模型中延迟了体内肿瘤形成。最后，在人类乳腺癌组织中，我们验证了炎症-IKKε 与细胞代谢改变之间的联系。总之，我们确定了将肥胖驱动的炎症与乳腺癌联系起来的途径，以及降低与肥胖相关的乳腺癌风险的潜在治疗策略。